thyroid neoplasia (Table 3-4). As in the case of tumor-suppressor gene loss, germline ret mutation may be viewed as removing one early rate-limiting step in multistage thyroid tumorigenesis such that the carrier individual is at increased risk of neoplastic development via the accumulation of further mutations in other genes. Again, greater-than-normal radiation risk to the target organ should be anticipated.
In the following sections, the above propositions are examined on the basis of available cellular, animal, and epidemiologic data.
Cellular data on heritable radiosensitivity in respect of cell inactivation have been reviewed recently (ICRP 1998). In brief, although there are isolated instances of cancer and/or radiotherapy patients showing clear evidence of radiosensitivity, it is only for AT and NBS that there is unambiguous evidence of profoundly increased radiosensitivity to cell killing associated with known human disorders of DNA damage response or repair and cancer. Claims for increased radiosensitivity in other cancer-prone disorders remain controversial and do not provide clear guidance on radiation cancer risk.
Although sensitivity to cell killing after radiation may at present not be a particularly useful surrogate for cancer risk, there are closer parallels between the induction of chromosome damage and cancer. Although not without some uncertainty, the data accumulating on the patterns of chromosomal radiosensitivity in human cancer-prone disorders are worthy of some attention. These data, considered by Scott and colleagues (1998) and reviewed by the National Radiological Protection Board (NRPB 1999) show that, compared with healthy controls, cells cultured from AT and NBS patients typically exhibit two- to threefold greater chromosomal radiosensitivity, but in some cytogenetic assays, the increased sensitivity can be up to tenfold (Taalman and others 1983; Taylor 1983). The NRPB has summarized a large body of cytogenetic data on which claims of associations between chromosomal radiosensitivity and human cancer susceptibility have been based. As in the case of cell killing, some of these claims remain controversial. More recent studies on the possible radiosensitivity of cells from breast cancer-susceptible BRCA1 and BRCA2 patients have also provided conflicting evidence (Buchholz and others 2002; Trenz and others 2002; Powell and Kachnic 2003). Of additional interest are the data on G2 cell cycle radiosensitivity, which among other findings suggest that AT heterozygotes are indeed radiosensitive and that up to 40% of unselected breast cancer cases also exhibit modestly elevated radiation-induced chromosome damage (Scott and others 1994; Parshad and others 1996). There is also some evidence of elevated chromosomal radiosensitivity in cells from patients with malignant gliomas (Bondy and others 1996) and colorectal cancer (Baria and others 2001).
In summary the evidence available on human chromosomal radiosensitivity suggests that AT and NBS may be up to tenfold more sensitive than normal; some uncertainty surrounds the chromosomal radiosensitivity of other cancer-prone disorders, but any such increase in sensitivity appears to be modest—not more than two- to threefold. Although critical data are lacking, it is a reasonable assumption that, in general, a heritable increase in chromosomal radiosensitivity would be associated with increased radiation cancer risk, albeit with possible differences in the response of different tissues. Data from G2 chromosomal radiosensitivity assays are generally supportive of this association, but some data remain controversial.
The experimental data available about the impact of heritable factors on radiosensitivity and tumorigenesis derive principally from studies on the genetic homologues of some of the human disorders listed in Tables 3-3 and 3-4. These studies are summarized in Table 3-5 with references.
Although there are some differences in the patterns of phenotypic expression, in the main the rodent genetic homologues of AT, Li-Fraumeni syndrome (LFS), familial adenomatous polyposes, neroid basal cell carcinoma syndrome (NBCCS), and tuberous sclerosis recapitulate many of the features of their human counterparts. In respect of early responses, Atm−/− mice show extreme radiosensitivity; there is also evidence of moderate in vivo radiosensitivity in Atm+/− mice. Studies with Atm+/− knockout mice (Barlow and others 1999) provided evidence of increased in vivo radiosensitivity but failed to demonstrate differences in radiation induced tumorigenesis between +/− and +/+ genotypes. However, more recent data on spontaneous tumorigenesis (Spring and others 2002) imply that such studies are best conducted with Atm knock-in mice, which recapitulate known human mutations.
Data on BRCA1- and BRCA2-deficient mice have yet to provide clear evidence on the role of these genes in radiation tumorigenesis. The principal benefit of the referenced studies noted in Table 3-5 is the provision of a growing association between the Brca genes, Rad51, cell cycle perturbation, and DNA damage response.
The most valuable animal genetic data on radiation tumorigenesis have been developed from studies on mice heterozygously deficient in the tumor-suppressor genes Tp53, Apc, and Ptch and in a rat strain (Eker) heterozygously deficient in Tsc2 (see Table 3-5 for references). In all instances, the germline mutational loss of one copy of the respective tumor-suppressor gene leads not only to an increase in the rate of spontaneous tumorigenesis but also to increased sensitivity to the induction of the same tumor types by whole-body low-LET radiation with doses up to around 5 Gy.
These data provide strong support for the contention, discussed earlier, that the unshielding of tumor-suppressor